Chronic obstructive pulmonary disease (COPD) is one of the most important public health problems in the United States, because it affects over 24 million people, costs $50 billion per year and is the third leading cause of death. It has been known for almost 40 years that only ~15% of susceptible smokers will develop COPD. Despite this knowledge, very little progress has been made in identifying factors that contribute to susceptibility and how these factors manifest during pre-symptomatic stages of disease (Pre-COPD). Airway progenitor cells are critical for the maintenance of lung health because of their ability to restore normal airway structure and function following injury. The inability of the lungto return to normal in COPD suggests that airway progenitor function is impaired. Progenitor cells are defined by the ability to self-renew, meaning that they are able to replenish themselves, and by the ability to differentiate into all cell-types that normally populate their home tissue, a characteristic referred to as multipotentiality. We leveraged the NIH-funded Biomarker Study to determine the role of airway progenitor cells in COPD. Our preliminary data show that progenitor counts, self-renewal and multipotentiality are all decreased in COPD. Progenitor dysfunction manifests in vitro during air-liquid interface culture by generation of an abnormal epithelium characterized by altered ratios of mucous, basal and ciliated cells, and increased secretion of mucus. COPD develops slowly over years as small airways narrow and disappear causing lung function to decline. Despite the importance of this long pre- symptomatic period there is no definition of Pre-COPD. Our preliminary data indicate that progenitor counts can be used to diagnose Pre-COPD, because they separate current/ex-smokers into those with high-normal or low-normal lung function. Based on these data, we hypothesize that progenitor exhaustion, identified by low progenitor counts, characterizes a subgroup of normal subjects with Pre-COPD. We also hypothesize the converse that progenitor vigor, identified by high progenitor counts, characterizes a subgroup with resilience and lung health. This proposal will use a cross-sectional approach in Specific Aim 1 to determine the measure of progenitor function (e.g. count, self-renewal or mulltipotentiality) or combination of measures that best define resilience and Pre-COPD. In Specific Aim 2 a longitudinal study will be used to examine whether subjects with Pre-COPD have an accelerated decline in lung function compared to resilient subjects. In both aims, extensive molecular and clinical data will be used to characterize resilience and Pre-COPD on the whole organism, cell and molecular levels. The most important innovation of this proposal is the concept that vigorous airway progenitors are necessary for resilience and lung health, and that exhausted progenitors make the lung susceptible to external assault and development of COPD. This concept could have a direct impact on preventing COPD by identifying those who are susceptible to the effects of cigarette smoke. Armed with this knowledge smoking cessation and early treatment efforts could be focused on people with Pre-COPD.